RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database

Abstract

BackgroundRetinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumour in children and potential cause of blindness from therapeutic eye ablation, second tumours in germ line carrier's survivors, and even death when left untreated. The molecular scanning of RB1 in search of germ line mutations lead to the publication of more than 900 mutations whose knowledge is important for genetic counselling and the characterization of phenotypic-genotypic relationships.ResultsA searchable database (RBGMdb) has been constructed with 932 published RB1 mutations. The spectrum of these mutations has been analyzed with the following results: 1) the retinoblastoma protein is frequently inactivated by deletions and nonsense mutations while missense mutations are the main inactivating event in most genetic diseases. 2) Near 40% of RB1 gene mutations are recurrent and gather in sixteen hot points, including twelve nonsense, two missense and three splicing mutations. The remainder mutations are scattered along RB1, being most frequent in exons 9, 10, 14, 17, 18, 20, and 23. 3) The analysis of RB1 mutations by country of origin of the patients identifies two groups in which the incidence of nonsense and splicing mutations show differences extremely significant, and suggest the involvement of predisposing ethnic backgrounds. 4) A significant association between late age at diagnosis and splicing mutations in bilateral retinoblastoma patients suggests the occurrence of a delayed-onset genotype. 5) Most of the reported mutations in low-penetrance families fall in three groups: a) Mutations in regulatory sequences at the promoter resulting in low expression of a normal Rb; b) Missense and in-frame deletions affecting non-essential sequence motifs which result in a partial inactivation of Rb functions; c) Splicing mutations leading to the reduction of normal mRNA splicing or to alternative splicing involving either true oncogenic or defective (weak) alleles.ConclusionThe analysis of RB1 gene mutations logged in the RBGMdb has shown relevant phenotype-genotype relationships and provided working hypothesis to ascertain mechanisms linking certain mutations to ethnicity, delayed onset of the disease and low-penetrance. Gene profiling of tumors will help to clarify the genetic background linked to ethnicity and variable expressivity or delayed onset phenotypes.

Cell transcriptional state alters genomic patterns of DNA double-strand break repair in human astrocytes

“…Exon 20 contains several hotspots for recurrent mutations of high functional impact 37 . The other loci, including one located in exon 23 of Rb1 , had significantly lower mean γH2AX ratios, ranging from 0.72 to 1.01 (Fig.…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…One exception is in retinoblastoma where it has been found that low-penetrance RB1 mutations tend either to lead to a reduction in the amount of Rb protein produced (through promoter or splice site mutations) or yield a partially functional Rb molecule through missense mutation or in-frame deletion (Onadim et al 1992; Kratzke et al 1994; Bremner et al 1997; Otterson et al 1997; Scheffer et al 2000; Genuardi et al 2001; Harbour 2001; Klutz et al 2002; Lefévre et al 2002; Valverde et al 2005; Sánchez-Sánchez et al 2005; Sampieri et al 2006; Gámez-Pozo et al 2007; Park et al 2008; Hung et al 2011). Of particular interest is the category of temperature-sensitive mutations in the Rb pocket domain (ΔAsn480, Arg661Trp, Cys712Arg) whose ‘reversible fluctuations’ in a threshold level of Rb pocket-binding activity could be responsible for their characteristic low penetrance (Otterson et al 1999).…”

Alterations of the retinoblastoma gene in metastatic breast cancer

“…These exons were analyzed since they have the highest frequencies of nonsense mutations in retinoblastoma patients ([18] and http://rb1-lovd.d-lohmann.de/). In line with our findings using RT-PCR screening, we observed no mutations in these “hot spot” exons when analyzing the same samples using genomic DNA, indicating that the likelihood of any mutation escaping our cDNA sequencing analyses are negligible.…”